Autophagy is a fundamental cell biological process (1) with impact on aging, development, cancer, neurodegeneration, myodegeneration, and metabolic disorders (2), idiopathic inflammatory diseases and infection and immunity (3). Much of the physiological effects of autophagy are the result of degradative activities of autophagy (1), although biogenesis and secretory roles (4-6) of autophagy are beginning to be recognized (7). The execution of autophagy depends on factors collectively termed Atg such as Atg5 (1) and Beclin 1 (Atg6) (8) whereas regulation of autophagy responds to various inputs via mTOR, including presence of microbes (9), TAB2/3-TAK1-IKK signaling axis (10), and processes downstream of pattern recognition receptors and immune cytokine activation (3, 11-13).
In the context of its immunological functions, autophagy acts in four principal ways (14): (i) Autophagy cooperates with conventional PRRs, such as TLRs, RLRs, and NLRs, and it plays the role of both a regulator (11, 12, 15, 16) and an effector of PRR signaling (17-19). (ii) Autophagy affects presentation of cytosolic antigens in the context of MHC II molecules (20) in T cell development, differentiation, polarization and homeostasis (21, 22). (iii) Most recently, autophagy has been shown to contribute to both the negative (6, 7, 23-25) and positive regulation (6, 7) of unconventional secretion of the leaderless cytosolic proteins known as alarmins such as IL-1β and HMGB1. (iv) Autophagy can capture and eliminate intracellular microbes including M. tuberculosis (17, 26-29) as one of the first two bacterial species (26, 30) to be recognized as targets for autophagic removal. This has been recently shown to depend on a recognition and capture by adaptors that represent a specialized subset of pattern recognition receptors (PRR) termed sequestosome-like receptors (SLRs) (31).
M. tuberculosis is one of the first microbes recognized as being subject to elimination by immunological autophagy in ex vivo systems in murine and human macrophages (17, 22, 26, 27, 29). Although it has been shown that macrophages from Atg5fl/fl r LysM-Cre+ mice defective for autophagy in myeloid lineage fail to control M. tuberculosis H37Rv (32) the in vivo role of autophagy in control of M. tuberculosis has not been reported. Given the compelling reasons for testing whether autophagy matters in control of M. tuberculosis in vivo, here we used a mouse model of tuberculosis and employed transgenic mice deficient in Atg5 in the myeloid lineage including macrophages, a cell type parasitized by M. tuberculosis (33). We demonstrate that autophagy controls tuberculosis infection in vivo and uncover a parallel role of autophagy in preventing excessive inflammatory reactions in the host.
The notion of autophagy as a purely degradative pathway was recently challenged by the emergence of reports of the secretory function of autophagy by three independent groups on the secretion of Acb1 in yeast (25A,26A,32A) and IL-1β secretion in mammalian cells (17A,27A). These new developments assign to autophagy a non-degradative function manifested as unconventional protein secretion (FIG. 3A). Furthermore, it has become apparent that autophagy even more broadly intersects with protein trafficking to include effects on the constitutive biosynthetic pathway (23A), regulated exocytosis (19A), and alternative sorting of integral membrane proteins to the plasma membrane (28A).